Compositions and methods for producing anesthesia

ABSTRACT

The present invention relates to anesthetic compositions containing 1,1,2-trifluoro-2-chloro-2-bromoethyl difluoromethyl ether and 1,1,2-trifluoro-2-bromoethyl difluorochloromethyl ether, and to the method of anesthetizing warm blooded air breathing mammals by administering an effective amount of each anesthetic composition.

United States Patent [151 3,666,864 Terrell 1 May 30, 1972 COMPOSITIONS AND NIETHODS FOR [5 6] References Cited PRODUCING ANESTHESIA UNITED STATES PATENTS 1 u, r 1 [72] C Tem d M 3,449,504 6/1969 Terrell .....424 342 [73] Assignee: Airco, Inc., New York, NY. 3,469,011 6/1964 Terrell ..424/342 [22} Filed: 1970 Primary Examiner-Jerome D. Goldberg [21] Appl. N0.: 68,474 Att0rneyEdmund W. Bopp, H. Hume Mathews and Roger M. Rathbun Related US. Application Data [63] Continuation-in-part of Ser. No. 877,031, Nov. 14, [57] ABSTRACT 1969. abandoned, which is a Continuation-impart of The present invention relates to anesthetic compositions con- 712,903 1968' abandoned and taining l,l,Z-trifluoro-2-chloro-2-brom0ethyl difluoromethyl 712,912 1968 abandoredether and l,l,2-trifluoro-2-bromoethyl difluorochloromethyl ether, and to the method of anesthetizing warm blooded air [52] US. Cl ..424/342, 260/614 F breathing mammals by administering an ff ti amount f [51] Int. Cl. r ..A61k 13/00 each anesthetic composition [58] Field of Search ..424/342; 260/614 F 6 Claims, No Drawings COMPOSITIONS AND METHODS FOR PRODUCING ANESTHESIA DESCRIPTION OF THE INVENTlOn The present application is a Continuation-in-Part of pending US. application Ser. No. 877,031, filed Nov. 14, 1969, now abandoned, which was a Continuation-in-Part of U.S. application Ser. No. 712,903, filed Mar. 14, 1968, now abandoned and application Ser. No. 712,912, filed Mar. 14, 1968, now abandoned.

This invention relates to novel anesthetic compositions containing l,1,2-trifluoro-2-chloro-2-bromoethyl difluoromethyl ether and l,1,2-trifluoro-2-bromoethyl difluorochloromethyl ether, and to the use of each composition in producing anesthesia in anesthetic susceptible air breathing mammals. The compounds of the present invention have the following generic formula:

CF XOCF CFBrX where X 1-1 and Cl alternately, and one X is chlorine.

The compound 1,1,2-trifluoro-2-chloro-2-bromoethyl difluoromethyl ether has the following formula:

It is normally a clear, colorless liquid with a not unpleasant odor. It has the following physical properties: boiling point 82 C.; vapor pressure 125 mm at 30 C.; specific gravity 1.7; refractive index n 1.3514; and a molecular weight of 263.5. The compound is non-flammable, soda lime stable and is a potent anesthetic for inhalation anesthetic susceptible mammals.

The compound 1 ,1,2 trifluoro-2-bromoethyl difluorochloromethyl ether has the following formula: CF CIOCF hfbr. It is normally a clear, colorless liquid with a very slight odor. It has the following physical properties: boiling point 81 C.; vapor pressure 95 mm at C; specific gravity 1.7; refractive index n,, 1.3465 and molecular weight 263.5. The compound is non-flammable, soda lime stable, and is a potent anesthetic for inhalation anesthetic susceptible mammals. The compound is also easily miscible with other organic liquids including fats and oils and has useful solvent properties; for example, as a solvent for fluorinated olefins and other fluorinated materials such as fluoro waxes. It may be used to prepare pastes and dispersions of such materials useful for coatings and the like and may be used as a degreasing agent.

Each of the ether compounds is preferably prepared through the following series of reactions involving the stepwise chlorination and fluorination of 1,1,2 trifluoro-2- bromoethyl methyl ether: I

The compound 1,1,2 trifluoro-Zbromoethyl methyl ether is a well known material which can be prepared by reacting methanol CH OH and trifluorobromoethylene CF CFBr in the presence of dissolved metallic sodium. The reaction is preferably carried out at temperatures below C. in a vessel maintained under a slight positive pressure of nitrogen to prevent the entrance of air. On completion of the reaction the desired 1,1,2 trifluoro-2-bromoethyl methyl ether can be separated from the reaction mass and purified by fractional distillation under reduced pressure.

The 1,1,2 trifluoro-2-bromoethyl methyl ether precursor is then chlorinated to form Cl-lCl OCF CFClBr or CCl OCF C l-lFBr. The chlorination of Cl-l oCF Cl-lFBr should be carried out in either a fully or partially transparent vessel so that photo energy can be supplied to the reaction. Suitable sources of photo energy are incandescent, ultraviolet and fluorescent lamps and even strong sun light. In view of the ready availability, low cost and ease of handling of incandescent lamps they are preferred for use as'the illumination source.

The chlorination is carried out by bubbling gaseous chlorine into the liquid CH OCF CHFBr while it is strongly illuminated. The chlorine is added at the same rate at which it reacts which can be detemrined by checking for chlorine vapor in the effluent from the chlorinator. The reaction is ex othermic so cooling water should be supplied to the chlorination apparatus to control the reaction. The chlorination can be carried out at any temperature from 15 C. up to the boiling point of the chlorination mixture. Best results are usually found at 25-35 C. where the reaction rate is fast enough and the formation of by-products does not present a serious problem.

The effluent from the chlorination apparatus should be passed through a water scrubber to dissolve the HCl which is formed. The chlorination should be continued until approximately 2.5 moles of l-lCl per mole of starting ether are detected by titration of the dissolved HCl with a standard base. The extent of the chlorination can be controlled by the amount of chlorine bubbled through the ether and determined by the amount of effluent HCI. If too little HCl is evolved it indicates that the chlorination products are predominantly the mono or dichloro product. If too much HCl is determined it indicates that polychloro products have been formed or that the ether has decomposed into undesirable chlorinated reaction products.

The lower chlorination products can be separated from the reaction mass by fractional distillation followed by further chlorination in order to raise the yield of the desired product.

Following the chlorination the reaction mass can be separated by fractional distillation or by vapor phase chromatography. If distillation is employed it is recommended that the pressure be reduced in view of the high molecular weight of the products CHCI OCF CFCIBr and CCl OCF CHFBr. Excessive heating should obviously be avoided in view of the possibility of decomposing the desired product.

The thus prepared CHCI OCF CFCIBr or CCl,-,OCF Cl-lF Br should then be transferred to a reaction vessel that will not be attacked during the fluorination reaction. A stainless steel, copper, nickel, or platinum vessel would be quite suitable. A catalyst such as SbCl SnCl or SbF should be added to the chlorinated starting materials before beginning the fluorination. The fluorination reaction can be carried out by bubbling gaseous HF through the reaction mixture or by adding solid SbF to the mixture.

The fluorination reaction is preferably carried out at 0 C. Higher or lower temperatures can be employed; however, it has been found that higher temperatures produce undesirable reaction products while lower temperatures cause a slow rate of reaction.

The effluent from the fluorination apparatus should be passed through a water scrubber to collect the HCl which is formed during the reaction. The amount of HCl formed is equivalent to the number of chlorine atoms exchanged for fluorine. Too little l-lCl evolved indicates incomplete exchange. Too much HCl indicates either over fluorination or decomposition. The fluorination should be continued until approximately two moles of HCl are collected for each mole of CHCl OCF- FClBr or CCl OCF CHFBr indicating that two chlorine atoms have been exchanged. The preferred site for the fluorination is on the chlorine substituted methyl group resulting in the formation of CHF OCF CFClBr or CF ClOCF CHFBr depending on which chlorinated ether was used. The desired reaction product can be readily separated from the reaction mixture by fractional distillation.

EXAMPLE 1 SYNTHESIS OF CH OCF CFHBr Sodium (10 g) was dissolved in methanol (500cc) and CF CFBr (500 g) was added slowly with cooling (less than 30 C.) and stirring. A positive pressure of nitrogen was maintained in the flask so that no air was introduced into the system. On completion of the reaction, the reaction mixture was poured into water and the crude product (540 g) recovered was fractionally distilled at 100 mm to yield 475 g, b.p. 36 at 100 mm, n 1.3660. This product was 99 percent pure and was satisfactory for chlorination.

EXAMPLE 2 PREPARATION OF Cl-lC1 OCF CFClBr Approximately 1,000 grams of CH OCF CHFBr prepared as illustrated in Example 1, were added to a water jacketed chlorinator fitted with a thermometer, a DRY-ICE" cold finger type condenser and a fritted glass gas dispersion chlorine being bubbled through the solution which was exposed to a source of illumination. The effluent HCl was collected in a scrubber and aliquots were titrated with a standard base. The reaction was continued until 2.4 moles of HC] per mole of ether was titrated. Following the chlorination 887 g of material were recovered. The composition of the resulting material was determined by vapor phase chromatography and found to be:

41% CCI OCF CHF Br 25% CHCl OCF CFClBr Fractional distillation of this mixture gave 190 grams of CI-lCl OCF FCIBr, b.p. 70 C. at 50 mm, n 1.4230. Calculated for: C l-lBrCl F o; C, 12.15; H, 0.34; F, 19.2

Found: C, 12.45; l-l,0.38; F, 18.94

The fractional distillation of this mixture also gave 169 grams of CCl OCF- CI-IFBr; b.p. 7275 C. at 50 mm, n 1.4325.

Calculated for: C HBrCl F O', C, 12.15; H, 0.34; F, 19.2

Found: C, 12.03;H,0.33; F, 18.88

EXAMPLE 3 PREPARATION OF CHF OCF CFClBr A l-liter 3-necked stainless steel flask was fitted with a copper DRY-ICE cold finger condenser, a stainless steel stirring shaft and gland and a copper gas inlet tube. To the flask there was then added 50 grams of CHCl OCF- CFClBr as prepared in Example 2 and 2.5 grams of SbCl HF gas was then slowly bubbled through the stirred mixture which was maintained at 0 C. The reaction was run until 0.4 moles of HCl was collected, as indicated by the titration of the effluent HCl which was dissolved in water. Following the fluorination 25 grams of material were recovered. Fractional distillation using a 30 X 0.5 cm column packed with glass helices gave the pure product, b.p. 82 C., n 1.3514.- Calculated for:C l-lBrClF 13.7; H, 0.38; F, 36.2

Found: C, 13.66; H, 0.37; F,35.0

The structure of CHF OCF CFClBr was determined by elemental analysis and by n.m.r. and infrared spectra. EXAM- PLE 4 PREPARATION OF CF ClOcF CHFBr A l-liter 3-necked stainless steel flask was fitted with a copper DRY-ICE" cold finger condenser, a stainless steel stirring shaft and gland and a copper gas inlet tube. To the flask there was then added 50 grams of CCl ICF CI'IFBr as prepared in Example 2 and 2.5 grams of SbCl HF gas was then slowly bubbled through the stirred mixture which was maintained at 0 C. The reaction was run until 0.4 moles of l-lCl was collected, as indicated by the titration of the effluent l-lCl which was dissolved in water. Following the fluorination 25 grams of material were recovered. Fractional distillation using a 30 X 0.5 cm column packed with glass helices gave the pure product, b.p. 81 C., n 1.3465. Calculated for: C l-lBr ClF O: C, 13.7; H, 0.38; F, 36.2

Found: C, 13.87; H, 0.40; F, 36.2

The structure of CF ClOCF CI-lFBr was determined by elemental analysis and by n.m.r. and infrared spectra.

In order to determine the potency of 1,1,2 trifluoro-2- chloro-2-bromoethyl difluoromethyl ether and 1,1,2 trifluoro- 2-bromoethy1 difluorochloromethyl ether as inhalation anesthetics in combination with oxygen a series of tests were carried out on mice. The ether compounds tested were at least 99.5 percent pure as determined by vapor phase chromatography.

Groups of five mice were placed into a jar and exposed to a concentration of 1.25 percent by volume of CHF OCF C FClBr. After an average induction time of 2.3 minutes, which was free of excitation, the mice were anesthetized. During the period of anesthesia the mice showed no change in respiration and no visible untoward effects. A good anesthetic syndrome was produced and the mice were maintained in a light plane of anesthesia. Some peripheral vasodilation was noted. The mice recovered in about 2.45 minutes following removal from the jar and showed no after effects.

Groups of five more mice were then given a similar test with 2.5 percent by volume of the compound. After an average induction time of 1.35 minutes an excellent anesthetic syndrome was produced. Anesthesia was deep and relaxation excellent. The respiration was slightly labored and some peripheral vasodilation was noted. The induction period was very smooth with no apparent excitation. On removal from the jar the mice fully recovered in about 7 minutes Groups of five mice were also placed into a jar and exposed to a concentration of 1.25 percent by volume of CF CIOCF CHFBr. After an induction time of 4.3 minutes, which was free of excitation, the mice were anesthetized. During the period of anesthesia the mice showed no change in respiration and no visible untoward effects. A good anesthetic syndrome was produced and the mice were maintained in a light plane of anesthesia. The mice recovered in 1.3 minutes following removal from the jar and showed no after effects.

Groups of five more mice were then given a similar test with 2.5 percent by volume of the compound. After an induction time of 1.2 minutes an excellent anesthetic syndrome was produced. Anesthesia was deep and relaxation excellent. The respiration and color were normal and no peripheral v'asodilation was noted. The induction period was very smooth with no apparent excitation. On removal from the jar the mice fully recovered in 2.5 minutes.

The compound 1,1,2 trifluoro-2-chloro-2-bromoethyl difluoromethyl ether and 1,1,2 trifluoro-Z-bromoethyl difluorochloromethyl ether exhibit excellent anesthetic properties in inhalation anesthetic susceptible mammals. The compounds are non-flammable and soda lime stable. Each compound lends itself to effective use as an inhalant anesthetic in respirable mixtures containing life-supporting concentrations of oxygen. In addition, studies with the agents have shown that they are highly potent, afford good muscular relaxation, are non-toxic, have a high margin of safety, afford rapid induction free of excitation and rapid recovery, and afford ease of control of the level of anesthesia.

The effective amount of CI-lF OCF CFClBr and CF ClOCF- CI-IFBr to be employed depends on the level of anesthesia to which the mammal is to be brought, the rate at which anesthesia is to be induced, and the length of time over which anesthesia is to be maintained. Volume percentages of CHF OCF CFClBr or CF CIOCF CI-IFBr in oxygen from a fraction of a percent up to several percent, can be employed. The person controlling the anesthesia can easily regulate the amount of the particular ether to be used, starting with a small amount and gradually increasing the amount until the desired plane of anesthesia is reached. By then monitoring the physical properties of the mammal, as is the usual procedure, the duration and plane of anesthesia can be readily controlled.

It should be understood that the foregoing disclosure relates only to preferred embodiments of the invention and that it is intended to cover all changes and modifications of the examples of the invention herein chosen for the purpose of the disclosure which do not constitute departure from the spirit and scope of the invention.

1 claim:

susceptible mammal which comprises administering by inhalation to said mammal an effective amount of inhalant anesthetic compound of the formula CF,XOCF,CFBrX wherein X is alternately chlorine and hydrogen, one X is chlorine, along with sufiicient oxygen to support life.

5. The method of anesthetizing an inhalation anesthetic susceptible mammal as set forth in claim 4 wherein the inhalant anesthetic has the formula CHI- OCF CFCIBr,

6. The method of anesthetizing an inhalation anesthetic susceptible mammal as set forth in claim 4 wherein the inhalant anesthetic has the formula CF ClOCF CHFBr. 

2. An inhalant anesthetic composition as set forth in claim 1 wherein the inhalant anesthetic compound is CHF2OCF2CFClBr.
 3. An inhalant anesthetic composition as set forth in claim 1 wherein the inhalant anesthetic compound is CF2ClOCF2CHFBr.
 4. The method of anesthetizing an inhalation anesthetic susceptible mammal which comprises administering by inhalation to said mammal an effective amount of inhalant anesthetic compound of the formula CF2XOCF2CFBrX wherein X is alternately chlorine and hydrogen, one X is chlorine, along with sufficient oxygen to support life.
 5. The method of anesthetizing an inhalation anesthetic susceptible mammal as set forth in claim 4 wherein the inhalant anesthetic has the formula CHF2OCF2CFClBr.
 6. The method of anesthetizing an inhalation anesthetic susceptible mammal as set forth in claim 4 wherein the inhalant anesthetic has the formula CF2ClOCF2CHFBr. 